Pharmaceutically active compounds may be formulated for administration by numerous routes. Typically, the appropriate route will depend on the disease being treated, the chemical and physical properties of the pharmaceutically active substance as well as the subjects to be treated. Suitable pharmaceutical formulations include those for oral, rectal, nasal, topical (including buccal, sub-lingual, and transdermal), vaginal or parenteral (including intramuscular, sub-cutaneous, intravenous, and directly into the affected tissue) administration or in a form suitable for administration by inhalation or insufflation. Pharmaceutical compositions for the treatment of cancer typically have been injectable, parenteral formulations for intravenous infusion of the pharmaceutically active compound. Generally, use of intravenous formulation has been indicated because of the cytotoxic nature of the anticancer formulation and/or the weakened condition of the patient. Anti-cancer solid dosage forms have been available in tablet form, for example Alkeran®, Leukeran®, Myleran®, Purinethol®, Tabloid®, and recently Xeloda®, but these have been the exception rather than the norm.
Tablets offer several advantages to both the manufacturer and to the patient. Tablets may be manufactured economically and are conveniently shipped, stored and dispensed. The patient can take advantage of a dosage form, which can be produced with an accurate dosage and has ease of administration and portability.
4-Quinazolinamines as dual inhibitors of the protein tyrosine kinases EGFR (Epithelial Growth Factor Receptor—also known as erbB-1) and erbB-2 have been disclosed in International Patent Application PCT/EP99/00048 filed Jan. 8, 1999, and published as WO 99/35146 on Jul. 15, 1999. The anhydrous and monohydrate ditosylate forms of specific 4-quinazolinamines were disclosed in International Patent Application PCT/US01/20706 filed Jun. 28, 2001, and published as WO 02/02552 on Jan. 10, 2002.
Of particular interest is N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate. This compound is now in development as GW572016 in the treatment of various cancers, including breast, lung, bladder, head and neck, and gastric cancers. GW572016 has poor flow characteristics and is poorly soluble in aqueous media over the physiologically relevant pH range. Typically, for a pharmaceutical composition containing a drug having poor solubility in water and a high drug load, it is difficult to maintain the high dissolution properties and good flow characteristics needed for typical pharmaceutical manufacturing processes. Further, due to the poorly soluble active ingredient, high drug dissolution is required to achieve acceptable bioavailability. The present inventors have now identified a novel oral pharmaceutical formulation containing as an active ingredient a 4-quinazolinamine, which is effective as an EGFR and/or erbB2 protein tyrosine kinase inhibitor. Such a pharmaceutical formulation produced by fluid bed granulation provides high drug dissolution while maintaining good flow characteristics during processing.